LAURA SILVESTRI (MILAN)
ERYTHROPOIESIS AND IRON METABOLISM INTERACTION
Terminal erythropoiesis, the process that generates red blood cells under erythropoietin
stimulation, is highly dependent upon body iron concentration, as exemplified by the
development of anemia when serum iron drops below a critical threshold. Since about 80%
of circulating iron (in the form of diferric transferrin, 2Fe-TF) is utilized for heme synthesis and
hemoglobin production, erythroid cells have developed strategies to secure their iron supply
and to regulate their function according to iron availability.
The regulation of iron homeostasis is dependent on hepcidin, a peptide hormone produced
by the liver that negatively controls serum iron levels by blocking the function of the iron
exporter ferroportin on enterocyte and macrophage membrane (Nemeth et al., 2004;
Aschemeyer et al., 2018). When hepcidin levels are high, ferroportin function is blocked and
both dietary iron uptake and macrophage release are reduced. On the contrary, low hepcidin
levels favor iron entry into the circulation. By controlling systemic iron, hepcidin indirectly
controls erythropoiesis. The reverse occurs in a mutual crosstalk between erythropoiesis and
the iron hormone.
The existence of an “erythroid regulator” that promotes iron influx into the blood stream was
postulated several years ago based on ferrokinetic studies in patients (Finch C. Blood 1994).
Later it was demonstrated that this occurs through hepcidin inhibition (Pak et al., Blood 2006).
Several potential “erythroid regulators” were proposed in the last years, as GDF15 (Tanno et
al., 2007) and TWSG1 (Tanno et al., 2009); however, their function was not substantiated in
vivo. The main erythroid regulator proved to be erythroferrone (ERFE, also named
myonectin), a tumor necrosis factor-related protein that inhibits hepcidin and increases iron
availability when erythropoiesis is stimulated as after hemorrhage, erythropoietin
administration (Kautz et al., 2014) and even in pathologic conditions as in ineffective
erythropoiesis (Kautz et al., 2015). In mice with partial or total genetic inactivation of ERFE,
the recovery from anemia after blood loss is delayed because of the reduced iron availability
secondary to the inappropriately high hepcidin levels (Kautz et al., Nat Med 2014). The
mechanism of action of ERFE is a transcriptional downregulation of hepcidin mediated in part
by the inhibition of the BMP-SMAD pathway, the main signaling pathway regulating hepcidin
expression in hepatocytes (Silvestri et al., 2019). This is due to the ability of ERFE to bind and
sequester BMP ligands, as BMP6 (Arezes et al., 2018), one of the main hepcidin activator
(Meynard et al., 2009; Andriopoulos et al., 2009). If anemia persists and in case of severe
hypoxia, other cells as macrophages, platelets and endothelial cells can contribute to hepcidin
inhibition releasing the platelet-derived growth factor-subunit B (PDGF-BB) (Sonnweber et al.,
2014). Another mechanism that contributes to hepcidin downregulation and that anticipates
the ERFE effect when EPO-EPOR signaling is activated in erythroid cells is the upregulation of
the 2Fe-TF receptor TFR1. High levels of TFR1, on one hand, increase iron uptake for Hb
synthesis, while on the other transiently reduce circulating iron, leading to hepcidin inhibition
(Artuso, Pettinato et al., 2018).
Erythroid cells express high levels of TFR1, responsible to supply iron mainly to heme
production and Fe-S cluster machinery. In iron deficiency, downregulation of the Fe-S cluster
biogenesis affects heme synthesis by: i) decreasing the activity of two enzymes that use the
Fe-S cluster as prosthetic group, as aminolevulinic acid dehydratase (ALAD), which catalyzes